The role of fatty acids in neurodegenerative diseases: mechanistic insights and therapeutic strategies

Nov 14, 2025Journal of lipid research

How Fatty Acids May Affect Brain Degeneration and Possible Treatments

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Abstract

Short-chain fatty acids generated by gut microbiota may regulate neuroinflammation and blood-brain barrier integrity.

Fatty acids (FAs) have diverse roles in neurodegenerative diseases like Alzheimer's and Parkinson's.
Short-chain FAs influence gut-brain communication and immune responses through epigenetic changes.
Medium-chain FAs may enhance energy metabolism and neuromuscular function in models of amyotrophic lateral sclerosis.
Long-chain polyunsaturated fatty acids, such as DHA and EPA, support neuronal health by maintaining membrane integrity and reducing oxidative stress.
Certain saturated and n-6 fatty acids could worsen neurodegeneration by promoting inflammation and oxidative damage.
Fatty acids are implicated in critical pathological processes including mitochondrial dysfunction and blood-brain barrier disruption.

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FAs play multifaceted roles in neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This review systematically summarizes current understanding of FA metabolism and its diverse implications in neurodegenerative diseases pathology. Short-chain FAs, primarily generated by gut microbiota, regulate neuroinflammation, gut-brain communication, and blood-brain barrier integrity via epigenetic modifications and immune modulation. Medium-chain FAs exhibit therapeutic potential by improving energy metabolism and neuromuscular function, particularly in amyotrophic lateral sclerosis models. Long-chain PUFAs, notably DHA and EPA, contribute to neuronal membrane integrity, synaptic plasticity, and antioxidant defense, mitigating oxidative stress and neuroinflammation. Conversely, saturated and certain n-6 FAs may exacerbate neurodegeneration through proinflammatory and oxidative pathways. Emerging evidence highlights FA involvement in key pathological processes such as lipid peroxidation, mitochondrial dysfunction, ferroptosis, and blood-brain barrier disruption. Therapeutically, targeted supplementation, dietary modification, microbiome manipulation, and advanced nanotechnology-based delivery systems are promising strategies. Nevertheless, precise therapeutic efficacy depends critically on disease stage, dosage, genetic background, and individual metabolic context. Integrating personalized medicine with precision nutritional strategies and novel drug-delivery platforms offers promising avenues to translate FA-based interventions into clinical practice, potentially improving patient outcomes in the aging global population.

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